2-methyl-3-p-toluenesulfonoxy-4-p-toluenesulfonylaminomethyl-5-phosphonoxymethylpyridine and intermediates therefor



Patented Aug. 22, 1950 UNITED STATES PATENT OFFICE 2i METHYL 3 P TOLUENESULFONOXY L P-TOLUENESULFONYLAMNOMETHYIM E-PHOSPHONDXYMETHYLPYRIDINE AN INTERMEDIATE'S THEREFOR Dorothea Hey! Hoffman, Rahway', N. J assignor to Merck .& Co.,. Inc., Rahway, N. J., a corporation of New Jersey N Drawing. Application February 19', 1949. Serial No. 77,446

1 2' This invention. relates to the. preparation of a phonoxymethylpyridine is useful as a growth new chemical compound;. 2-methyI-3-p-toluenefactor for certain microorganisms and has been sultonoxy 4 ptoluene-sulfonyiaminomethyh found to form a bright red color when coupled .5--phos-pho-noxymethylpyridina. It is also conwithdiazotized aniline.

cerned withthe preparation of the calcium salt A suspension of the caicium salt of 2-methylof 2 methyls-3-hydroxy-4z-aminomethyls5-phos- 3 hydroxy 4 aminomethyl 5 phosphonoxyphonoxymethylpyridine produced as an intermemethylpyridine in sodium hydroxide may be diate in my process; treated with a solution of p-toluenesulfonyl chlo- The new chemical? compound withwhich my ride in ether. After the mixture is centrifuged, invention is concerned, the calcium salt of 2- the ether layer is discarded. From the aqueous methyl 3- hydroxyaminomethyl 5-phoslayer is recovered 2-methyl-3-p-toluenesulfophonoxymethylpyridine is useful as a growth noXy 4 p-toluenesulfonylaminomethyl-5-phosfactor for certain microorganisms and has been phonoxymethylpyridine which has the structural found: to form a bright red color when coupled formula: with diazotized aniline. It has; also been found so o mcm that the novel compound 2-methyl-3 p-toluenesulfon'oxy 4 p toluenesulfonylaminomethyl- 5 phosphonoxymethylpyridine definitely establishes the structure for pyrid'oxamine phosphate H30 N (2 methyl 3 -hydroxy-4-aminomethylF5'-phos= phonoxymethylpyridine). This novel chemical compound, 2-methyl-3-p- In preparing my novel chemical compounds,. I toluenesulfonox 4 p toluenesulfonylaminoutilize as the starting material, 2-m'ethylt-3-hymethyl-5 phosphonoxymethylpyridine definitely drOXy 4 aminomethyl 5-hydroxymethylpyriestablishes the structure for pyridoxamine phosdine dih-ydrohalide; which has the structural forphate (2 methyl 3-hydroxy-4-aminomethyl-5 mula: ph'osphonoxymethylpyridine), since it is found N that the phenolic hydroxyl group is no longer HO GHOH. free as shown by a, negative ferric chloride test. 2 The preparation of my novel compound and If the novel intermediate chemical compoundob- H3O\N/ 2 tained during the course of the reactions by 1 v which they maybe secured may be illustrated by and phosphorus oxyhahde. The reaction 1 the following specific examples. It should be med out by treatmg aqumus solution of noted, of course that these examples are in.-

methyl ehydroxy-4-a i o t tended to be illustrative of the methods and promethylpyridme dihydrohalide with phosphorus cedures utilized in preparing these compounds,

oxyhwde f temperatures below Hydro and that they are not intended to be restricted or gen halide is removed from the solut1on and said to be regarded as embgdying the only way in solution is neutralized with a suspension of calwhich my novel compounds an be formed and cium carbonate in water. The calcium hydro- 4O recovered gen phosphate and calcium bicarbonate salts EXAMPLE 1 which separate from the solution are removed and the filtrate is diluted with ethyl alcohol and Preparation of the calcium salt of 2-methyl-3- chilled. This results in the precipitation of a hydromy 4 aminomethyl- 5 phosphonomywhite gelatinous material, the calcium salt of 2- methylpyridine methyl 3 hydroxy 4 aminomethyl 5-phos- In a flask equipped with a mechanical stirrer phonoxymethylpyndme whlch may be ldentlfied and immersed in a Water bath was placed a soluby the following formula: tion of 4.28 grams of 2-methyl-3-hydroxy-4- aminomethyl-5-hydroxymethylpyridine dihydro- HO CHzOPOaCa chloride dissolved in 25 cc. of water. The solution was stirred while 15 cc. of phosphorus oxy- Ha N chloride was added dropwise at such a rate that the temperature did not rise above 50 C. The This new chemical compound, the calcium salt addition required approximately fifty minutes, of 2 methyl-3-hydroxy-4-aminomethyl-5-phos- ,5 and the mixture was then stirred for about twenty minutes. After evacuation of the mixture to remove as much hydrogen chloride as possible, the solution was diluted with 35 cc. of water. A suspension of 90 grams of calcium carbonate in 40 cc. of water was then added to the reaction mixture with occasional stirring at 5-10 C. until the reaction mixture was adjusted to a pH of 5-6. After an hours chilling, the precipitated calcium phosphate and calcium bicarbonate salts were collected on a filter and washed with 40 cc. of ice water. The combined filtrate and washings were cleared by filtration through a fine sintered glass funnel which resulted in 65 cc. of light greenish-yellow solution. This solution was then diluted with 200 cc. of ethyl alcohol and chilled. The white gelatinous material which,

EXAMPLE 2 Preparation of 2-methy -3-p-tolucnesulfonowy- 4 toulenesulfonylaminomethyl 5 phosphonowymethyZ-pyridine To a suspension of 0.49 gram of the calcium salt of 2-methyl-3-hydroxy-i-amino-methyl-5- phosphonoxymethylpyridine in 10 cc. of N so dium hydroxide was added a solution of 1 gram of p-toluenesulfonyl chloride in 10 cc. of ether. The reaction mixture was shaken for four hours and then centrifuged. The ether layer was separated, and the suspension in water was washed three times with ether. The resulting mixture consisted of three layerstwo solid layers sepa-- rated by a solution. The bottom, solid layer was separated, suspended in water, cooled in an ice bath, and acidified with hydrochloric acid. I'he sticky mass which resulted was removed and dissolved in methyl alcohol. The sticky mass dissolved at once, and crystals rapidly separated from the solution. The solution was filtered and washed with methyl alcohol and ether.- There was secured 2-methyl-3-p-toluenesulfonoxy-4- p toluenesulfonylaminomethyl-5-phosphonoxymethylpyridine having a melting point of 189-190 C. (dec.). In this tosyl derivative the phenolic hydroxyl group is no longer free, as is shown by a negative ferric chloride test.

Analysis calculated for CzzHzsNaOsPS: C, 47.47; H, 4.53; N, 5.03; P, 5.57; S, 11.52. Found: C, 47.17; H, 4.71; N, 5.64; P, 5.88; S, 12.52.

It should be understood that various changes may be made in m process as herein described without affecting the improved results obtained. Thus, various modifications of conditions as to time, temperature, alkalinity, acidity, etc., and various changes in procedure differing from those herein given as illustrative of the preferred embodiments of my invention may be made without departing from the scope thereof. Accordingly, the scope of my invention is to be determined in accordance with the prior art and appended claims.

I claim:

l. The calcium salt of 2-methyl-3-hydroxy-4- aminomethyl-5-phosphonoxymethylpyridine.

2. 2 methyl 3 p toluenesulfonoxy-4-ptoluenesulfonylaminomethyl 5 phosphonoxymethylpyridine.

3. The process which comprises reacting 2- methyl 3 hydroxy 4 aminomethyl 5 hydroxymethylpyridine hydrochloride with phosphorus oxychloride in aqueous medium, neutralizing the reaction mixture with calcium carbonate, adding alcohol to the filtrate of said mixture whereby precipitating the calcium salt of 2 methyl 3 hydroxy 4 aminomethyl 5- phosphonoxymethylpyridine, recovering the latter precipitate, reacting a sodium hydroxide suspension of said precipitate with an ether solution of p-toluenesulfonyl chloride and recovering 2 methyl 3 p -toluenesulfonoxy 4 ptoluenesulfonylaminomethyl 5 phosphonoxymethylpyridine.

4. The process which comprises reacting 2- methyl 3 hydroxy 4 aminomethyl 5 hydroxymethylpyridine hydrochloride with phosphorus oxychloride in aqueous solution, neutralizing the reaction mixture with calcium carbonate, adding alcohol to the filtrate of said mixturewhereby precipitating the calcium salt of 2- methyl 3 hydroxy 4 aminomethyl 5 phosphonoxymethylpyridine and recovering the latter precipitate.

5. The process which comprises reacting a sodium hydroxide suspension of the calcium salt of 2 methyl 3 hydroxy 4 aminomethyl 4 5- No references cited. 

3. THE PROCESS WHICH COMPRISES REACTING 2METHYL - 3 - HYDROXY - 4 - AMINOMETHYL - 5 - HYDROXYMETHYLPYRIDINE HYDROCHLORIDE WITH PHOSPHORUS OXYCHLORIDE IN AQUEOUS MEDIUM, NEUTRALIZING THE REACTION MIXTURE WITH CALCIUM CARBONATE, ADDING ALCOHOL TO THE FILTRATE OF SAID MIXTURE WHEREBY PRECIPITATING THE CALCIUM SALT OF 2 - MTHYL - 3 - HYDROXY - 4 - AMINOMETHYL - 5PHOSPHONOXYMETHYLPYRIDINE, RECOVERING THE LATTER PRECIPITATE, REACTING A SODIUM HYDROXIDE SUSPENSION OF SAID PRECIPITATE WITH AN ETHER SOLUTION OF P-TOLUENESULFONYL CHLORIDE AND RECOVERING 2 - METHYL - 3 - P -TOLUENESULFONOXY - 4 - PTOLUENESULFONYLAMINOMETHYL - 5 - PHOSPHONOXYMETHYLPYRIDINE. 